Enantioselective Synthesis of Nitrogen–Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel–Crafts Alkylation Reaction

Abstract

Nitrogen–nitrogen bonds containing motifs are ubiquitous in natural products and bioactive compounds. However, the atropisomerism arising from a restricted rotation around an N–N bond is largely overlooked. Here, we describe a method to access the first enantioselective synthesis of N–N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel–Crafts alkylation reaction. A wide range of axially chiral N–N bisazaheterocycle compounds were efficiently prepared in high yields with excellent enantioselectivities via desymmetrization and kinetic resolution. Heating experiments showed that the axially chiral bisazaheterocycle products have high rotational barriers.

Organocatalytic Atroposelective Synthesis of N−N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation

“…Only recently, during our investigations, two innovative strategies emerged for the catalytic atroposelective synthesis of N−N axially chiral molecules (Scheme 1). [23] One is Lu and Houk's strategy of dynamic kinetic resolution via asymmetric organocatalysis (Scheme 1a), [23a] and the other is Liu and Lu's strategy of desymmetrization via asymmetric metal catalysis (Scheme 1b) [23b] . Based on these two strategies, N−N axially chiral 1‐aminopyrroles, 3‐aminoquinazolinones, and bispyrroles were efficiently synthesized in an atroposelective manner.…”

Catalytic Enantioselective Synthesis of C–N Atropisomeric Heterobiaryls

“…However, in 2021 Lu, Liu, and co-workers disclosed the first catalytic asymmetric approach (Scheme 32). 39 Their strategy resembles that of Wang, Tan, and coworkers (Scheme 18), 4d where catalytic activation of an electrophilic oxomalonate enables desymmetrisation of a pre-formed axial bond. Treatment of pre-formed bipyrroles 116 with oxomalonates 117 resulted in alkylation at the 3position of the more electron-rich and less hindered upper pyrrole (as drawn), and the presence of Cu(OTf) 2 and bisoxazoline ligand 119 led to the products 118 being formed in high yields and enantioselectivities.…”

Synthesis of Atropisomeric Hydrazides by One‐Pot Sequential Enantio‐ and Diastereoselective Catalysis

“…However, despite their ever‐increasing importance as bioactive molecules, materials, and chiral ligands [3] (Figure 1a), direct enantioselective synthesis was not explored until recently, when several preparations of N−N atropisomers were disclosed in rapid succession (Figure 1b). Liu and Lu synthesized 1,1′‐bipyrrole atropisomers through dissymmetric Friedel–Crafts alkylation using a Cu‐bisoxazoline‐catalyst [4] . The groups of Lu and Houk reported access to 1‐aminopyrroles and 3‐aminoquinazolinones by Brønsted base catalysis [5] .…”

“…Liu and Lu synthesized 1,1'-bipyrrole atropisomers through dissymmetric Friedel-Crafts alkylation using a Cu-bisoxazolinecatalyst. [4] The groups of Lu and Houk reported access to 1aminopyrroles and 3-aminoquinazolinones by Brønsted base catalysis. [5] Li realized the N-acylation and N-alkylation reactions of quinazolinone-type benzamides.…”